Muscle lipid metabolism & triacylglycerol accumulation

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DESCRIPTION (provided by applicant): Intramuscular triacylglycerol (TAG) content is increased with obesity and negatively associated with insulin sensitivity. The mechanisms that account for increased intramuscular TAG deposition with obesity are not clear at this time. The purpose of this proposal is to examine lipid metabolism in human skeletal muscle from obese individuals and discern the mechanism(s) responsible for intramuscular TAG accumulation. It is our primary hypothesis that human skeletal muscle from obese individuals partitions free fatty acids towards lipid storage resulting in intramuscular TAG accumulation. This hypothesis is based on our preliminary work, where in obese skeletal muscle we observed reduced free fatty acid uptake and oxidation, and a majority of uptake was partitioned to storage. These data form the basis for our working hypothesis, that TAG synthetic capacity is increased with obesity, promoting lipid storage in skeletal muscle. Our secondary hypothesis is that weight loss, which is known to decrease intramuscular lipid, will correct the defect(s) in lipid metabolism responsible for TAG accumulation. The specific aims of this proposal are to: 1) determine intramuscular TAG content and rates of TAG synthesis and hydrolysis in muscle from nonobese and obese individuals; 2)determine activity of rate-limiting enzymes of TAG synthesis and hydrolysis in the same tissue from specific aim 1; and 3)determine the effects of weight loss on intramuscular TAG content and capacities for TAG synthesis and hydrolysis in obese individuals.